Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity

Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibition. Among the other, trans -6 showed the most interesting biological profile, as it exhibited a strong pro-apoptotic activity in tumor cell lines in comparison with both of its parent compounds and a marked HDAC inhibition

Characterization of the complex locus of bean encoding polygalacturonase-inhibiting proteins reveals subfunctionalization for defense against fungi and insects.

Polygalacturonase-inhibiting proteins (PGIPs) are extracellular plant inhibitors of fungal endopolygalacturonases (PGs) that belong to the superfamily of Leu-rich repeat proteins. We have characterized the full complement of pgip genes in the bean (Phaseolus vulgaris) genotype BAT93. This comprises four clustered members that span a 50-kb region and, based on their similarity, form two pairs (Pvpgip1/Pvpgip2 and Pvpgip3/Pvpgip4). Characterization of the encoded products revealed both partial redundancy and subfunctionalization against fungal-derived PGs. Notably, the pair PvPGIP3/PvPGIP4 also inhibited PGs of two mirid bugs (Lygus rugulipennis and Adelphocoris lineolatus). Characterization of Pvpgip genes of Pinto bean showed variations limited to single synonymous substitutions or small deletions. A three-amino acid deletion encompassing a residue previously identified as crucial for recognition of PG of Fusarium moniliforme was responsible for the inability of BAT93 PvPGIP2 to inhibit this enzyme. Consistent with the large variations observed in the promoter sequences, reverse transcription-PCR expression analysis revealed that the different family members differentially respond to elicitors, wounding, and salicylic acid. We conclude that both biochemical and regulatory redundancy and subfunctionalization of pgip genes are important for the adaptation of plants to pathogenic fungi and phytophagous insects

Estimativa das Trocas Líquidas de co2 para Diferentes Coberturas de Solo em um Agroecossitema na Região Oeste do Pará, km77, em Santarém, PA

Estimativa das trocas líquidas de CO2 para diferentescoberturas de solo em um agroecossitema na região oestedo Pará, km77, em Santarém, P

Identification and characterization of a terphenyl derivative blocking the G1-S transition in neoplastic cells

Over the past years, we have been engaged in a project aimed at the discovery of either innovative antitumor lead candidates or chemical tools able to modulate specific molecular pathways of neoplastic cells. Thus, taking advantage of a parallel approach, we synthesized a small library of organic molecules containing the stilbene privileged structure or derived from it. We evaluated the antiproliferative and proapoptotic activities of all the compounds, as well as the effects on the cell cycle of some representative ones. After further investigations, a terphenyl derivative (TR14) showed the most interesting biological profile, being able to interfere with the cell cycle progression at the G1-S transition by blocking the phosphorylation of Rb and inducing cell differentiation in K562 cells. Considering that the G1/S checkpoint is controlled by the phosphorylation of Rb, in turn carried out by Cdk4-6/cyclin D and Cdk2/cyclin E, we then examined the effects of TR14 on the expression of these proteins. The results of these experiments will provide hints as to the molecular target of TR14. Methodologically, they will also allow us to validate a chemical biological \u201ctop-down\u201d protocol to the identification of both new biologically active compounds and their targets

Identification of a Terphenyl-Based Small Molecule That Induces Differentiation in Leukemia Cells

Because of our ongoing interest in finding new apoptosis-inducing agents, we are particularly intrigued by molecular scaffolds that allow the parallel synthesis of substituted derivatives. Actually, the parallel procedure is suitable for rapidly obtaining variously substituted analogs, particularly when structure-based design strategy is not applicable due to the lack of knowledge of a specific target. Thus, we recently synthesized a small library of resveratrol analogs, bearing the 3,5-dimethoxy motif at the A phenyl ring: many derivatives were more active than resveratrol as apoptosis-inducing agents in HL60 leukemia cells, and some of them were active toward resistant HL60R cells. Given these results, we aimed at increasing the structural diversity of the new molecules by synthesizing a second series of derivatives, which incorporate a phenyl ring as a bioisosteric substitution of the alkenyl bridge. Thus, through a Suzuky cross-coupling we obtained a small series of terphenyls that were tested on several leukemia cell lines. One of the new derivatives, TR9, behaved differently from the others, as it was able to block the cell cycle in G0-G1 phase and also to induce differentiation in acute myelogenous leukemia HL60 cells. Compared to resveratrol, the synthetic terphenyl I showed a more potent apoptotic and differentiating activity. Moreover, it was active on both multidrug resistance and Bcr-Abl expressing cells that were resistant to resveratrol

Identification of biphenyl-based hybrid molecules able to decrease the intracellular level of Bcl-2 protein in Bcl-2 overexpressing leukemia cells

With the aim of enhancing the structural complexity and diversity of an existing collection of bi- and terphenyl compounds, we synthesized hybrid molecules comprising of spirocyclic ketones (a complexity-bearing core) and bi/terphenyls (privileged fragments). Compounds 1, 3, 4, and 6 showed well-defined activity on apoptosis and differentiation, making them potential leads for development as new anticancer agents and chemical probes to study signaling networks in neoplastic cells

Atrioventricular canal defect in patients with RASopathies

Congenital heart defects affect 60-85% of patients with RASopathies. We analysed the clinical and molecular characteristics of atrioventricular canal defect in patients with mutations affecting genes coding for proteins with role in the RAS/MAPK pathway. Between 2002 and 2011, 101 patients with cardiac defect and a molecularly confirmed RASopathy were collected. Congenital heart defects within the spectrum of complete or partial (including cleft mitral valve) atrioventricular canal defect were diagnosed in 8/101 (8%) patients, including seven with a PTPN11 gene mutation, and one single subject with a RAF1 gene mutation. The only recurrent mutation was the missense PTPN11 c.124 A>G change (T42A) in PTPN11. Partial atrioventricular canal defect was found in six cases, complete in one, cleft mitral valve in one. In four subjects the defect was associated with other cardiac defects, including subvalvular aortic stenosis, mitral valve anomaly, pulmonary valve stenosis and hypertrophic cardiomyopathy. Maternal segregation of PTPN11 and RAF1 gene mutations occurred in two and one patients, respectively. Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation. In conclusion, our data confirm previous reports indicating that atrioventricular canal defect represents a relatively common feature in Noonan syndrome. Among RASopathies, atrioventricular canal defect was observed to occur with higher prevalence among subjects with PTPN11 mutations, even though this association was not significant possibly because of low statistical power. Familial segregation of atrioventricular canal defect should be considered in the genetic counselling of families with RASopathies. © 2013 Macmillan Publishers Limited. All rights reserved